DK167765B1 - ANALOGY PROCEDURE FOR PREPARATION OF 2-BETA-D-RIBOFURANOSYLSELENAZOLE-4-CARBOXAMIDE COMPOUNDS - Google Patents
ANALOGY PROCEDURE FOR PREPARATION OF 2-BETA-D-RIBOFURANOSYLSELENAZOLE-4-CARBOXAMIDE COMPOUNDS Download PDFInfo
- Publication number
- DK167765B1 DK167765B1 DK129983A DK129983A DK167765B1 DK 167765 B1 DK167765 B1 DK 167765B1 DK 129983 A DK129983 A DK 129983A DK 129983 A DK129983 A DK 129983A DK 167765 B1 DK167765 B1 DK 167765B1
- Authority
- DK
- Denmark
- Prior art keywords
- compound
- carboxamide
- preparation
- selenazole
- ribofuranosylselenazole
- Prior art date
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- 238000000034 method Methods 0.000 title claims description 16
- 238000002360 preparation method Methods 0.000 title claims description 8
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- DQWPFSLDHJDLRL-UHFFFAOYSA-N triethyl phosphate Chemical compound CCOP(=O)(OCC)OCC DQWPFSLDHJDLRL-UHFFFAOYSA-N 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-O triethylammonium ion Chemical compound CC[NH+](CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-O 0.000 description 1
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D421/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms
- C07D421/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms containing two hetero rings
- C07D421/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/20—Oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H5/00—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium
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- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
Description
i DK 167765 B1in DK 167765 B1
Den foreliggende opfindelse angår en analogifremgangsmåde til fremstilling af hidtil ukendte 2-0-D-ribofuranosylselenazol- 4-carboxamidforbindelser med farmakologisk virkning, især an* tisvulstvirkning og antiviral virkning.The present invention relates to an analogous process for the preparation of novel 2-O-D-ribofuranosyl selenazole-4-carboxamide compounds having pharmacological action, in particular antitumor and antiviral activity.
55
Bekæmpelse af ondartede svulster hos mennesker og dyr er fortsat et uopnået mål. Inden for de sidste adskillige årtier har ondartethedsforståelsen gjort betydelige fremskridt, men overvindelse af ondartethedens syg-10 domstilstand er ikke blevet opnået.Combating malignant tumors in humans and animals remains an unreachable goal. Within the last several decades, the understanding of malignancy has made significant progress, but overcoming the malignancy of the malignancy has not been achieved.
Konventionel behandling af både mennesker og andre værdifulde dyrearter, der er plaget af ondartede svulster, omfatter i øjeblikket kirurgisk bortskæring af svulsten, 15 lokal strålingsbehandling af det angrebne dyr og kemoterapi ved administration af et kemoterapeutisk middel til dyret. Døden af et betydeligt antal patienter, der er angrebet af ondartede svulster, skyldes ikke primærsvulsten, men i stedet metastaser fra primærsvulsten til 20 sekundære steder hos værten. Hvis en primærsvulst opdages tidligt, kan den normalt fjernes ved hjælp af kirurgi, stråling eller kemoterapi eller kombinationer deraf. Metastasekolonierne fra disse primærsvulster er imidlertid betydelig vanskeligere at opdage og fjerne, og den 25 mislykkede behandling af dem forbliver at være et alvorligt lægeligt problem.Conventional treatment of both humans and other valuable animal species plagued by malignant tumors currently includes surgical cutting of the tumor, local radiation therapy of the affected animal, and chemotherapy in the administration of a chemotherapeutic agent to the animal. The death of a significant number of patients affected by malignant tumors is not due to the primary tumor, but instead metastases from the primary tumor to 20 secondary sites of the host. If a primary tumor is detected early, it can usually be removed by surgery, radiation or chemotherapy or combinations thereof. However, the metastasis colonies from these primary tumors are significantly more difficult to detect and remove, and the 25 unsuccessful treatment of them remains a serious medical problem.
Svulster klassificeres normalt enten som godartede eller ondartede. Den ondartede svulst karakteriseres ved sin 30 evne til både at trænge ind i omgivende væv og at inficere fjerne steder via metastase. Visse organer er mere modtagelig eller udsatte for metastase end andre. Til denne gruppe vil lungerne, hjernen, leveren, ovarierne og binyrerne høre. Det har yderligere været forventet, 35 at både kirurgi og bestråling af en primærsvulst i visse tilfælde i virkeligheden fremmer metastase.Tumors are usually classified as benign or malignant. The malignant tumor is characterized by its ability to both penetrate into surrounding tissues and to infect distant sites via metastasis. Some organs are more susceptible or susceptible to metastasis than others. To this group, the lungs, brain, liver, ovaries and adrenal glands will belong. It has also been expected that in some cases both surgery and radiation of a primary tumor actually promote metastasis.
UiV ID/ /OO D IUiV ID / / OO D I
22
Som følge af nuværende cancerbehandlings manglende evne til på vellykket måde at bekæmpe den ondartede svulst og dens metastase, foreligger der et behov for yderligere kemoterapeutiske midler.Due to the inability of current cancer treatment to successfully fight the malignant tumor and its metastasis, there is a need for additional chemotherapeutic agents.
5 På lignende måde står der for tiden midler til rådighed til bekæmpelse og behandling af antivirale infektioner, men få af disse midler er klinisk anvendelige, og disse er kun aktive inden for et snævert område. På dette felt 10 foreligger der derfor også et behov for yderligere kemoterapeutiske midler, især for midler, der har såvel antiviral virkning som antisvulstvirkning.5 Similarly, agents are currently available to combat and treat antiviral infections, but few of these agents are clinically useful and are only active in a narrow range. Therefore, there is also a need in this field 10 for additional chemotherapeutic agents, especially for agents having both antiviral and anti-tumor effects.
Den foreliggende opfindelse angår en analogifremgangsmåde til 15 fremstilling af hidtil ukendte 2-/3-D-ribofuranosylselenazol-4-carboxamidforbindelser med den almene formel: 20 N-^Se R °(jH2 fy r20 OR1 25 hvori Ri og R2 hver er hydrogen, lavere alkanoyl eller benzoyl, og R3 er hydrogen,lavere alkanoyl, benzoyl eller 0' H0-P-;.The present invention relates to an analogous process for the preparation of novel 2- / 3-D-ribofuranosylselenazole-4-carboxamide compounds of the general formula: 20 N- See R ° (jH2 to r20 OR1 wherein R 1 and R 2 are each hydrogen, lower alkanoyl or benzoyl and R 3 is hydrogen, lower alkanoyl, benzoyl or O 'H0-P-;
30 OH30 OH
og når R3 er phosphono, fysiologisk acceptable salte deraf.and when R 3 is phosphono, physiologically acceptable salts thereof.
35 Foretrukne ved fremgangsmåden if^S« opfindelsen fremstillede forbindelser er følgende: DK 167765 B1 3 2-/3-D-r ibof uranosy Iselenazol-4-carboxamid, 2-(2,3,5-tri-0-acetyl-0-D-ribofuranosyl)-selenazol-4-carbox-amid, 2-0-D-ribofuranosyIselenazol-4-carboxamid-51-phosphat, og 5 2-0-D-ribof ur anozy Isel enazol-4-carboxam i d-5' -phosphat, natri umsalt .Preferred by the process of the invention are compounds as follows: DK 167765 B1 3 2- / 3-Dr ibof uranosy Iselenazole-4-carboxamide 2- (2,3,5-tri-O-acetyl-0-D (ribofuranosyl) selenazole-4-carboxamide, 2-O-D-ribofuranosylselenazole-4-carboxamide-51-phosphate, and 2-O-D-ribofur anozyl Isel enazole-4-carboxam in d-5 ' -phosphate, sodium salted.
Forbindelsen 2-0-D-ribofuranosylselenazol-4-carboxamid, i det følgende undertiden omtalt som forbindelse 1, har vist sig at 10 udvise signifikant antisvulstvirkning in vivo og signifikant antiviral virkning in vitro. Midler indeholdende denne forbindelse og/eller esterderivater med formlen I kan anvendes til behandling af ondartede svulster i varmblodede dyr. Anti-svulstegenskaberne hos 2-0-D-ribofuranosylselenazol-4-carbox-15 amid og dens afledte estere udnyttes ved administration til et varmblodet dyr af en effektiv mængde af et farmaceutisk middel indeholdende som aktiv bestanddel mindst ca. 0,1 vægt%, regnet i forhold til midlets samlede vægt, af mindst én forbindelse med formlen I.The compound 2-0-D-ribofuranosylselenazole-4-carboxamide, hereinafter sometimes referred to as compound 1, has been shown to exhibit significant anti-tumor effect in vivo and significant antiviral effect in vitro. Agents containing this compound and / or ester derivatives of formula I can be used to treat malignant tumors in warm-blooded animals. The anti-tumor properties of 2-O-D-ribofuranosylselenazole-4-carboxamide and its derived esters are utilized in administering to a warm-blooded animal an effective amount of a pharmaceutical agent containing as an active ingredient at 0.1% by weight, based on the total weight of the agent, of at least one compound of formula I.
2020
Midler indeholdende forbindelsen 1 og/eller esterderivater med formlen I kan endvidere anvendes til behandling af virale infektioner i varmblodede dyr. De antivirale egenskaber hos 2-0-D-ribofuranosylselenazol-4-carboxamid og estere deraf udnyttes 25 ved administration til et varmblodet dyr af en effektiv mængde af et farmaceutisk middel, der som aktiv bestanddel indeholder mindst ca. 1,0 vægt%, regnet i forhold til midlets samlede vægt, af mindst én forbindelse med formlen I.Furthermore, agents containing the compound 1 and / or ester derivatives of formula I can be used to treat viral infections in warm-blooded animals. The antiviral properties of 2-O-D-ribofuranosylselenazole-4-carboxamide and esters thereof are utilized by administration to a warm-blooded animal of an effective amount of a pharmaceutical agent containing as an active ingredient at least approx. 1.0% by weight, based on the total weight of the agent, of at least one compound of formula I.
30 Særlige betydninger af R*, R2 og R3 i forbindelserne ifølge opfindelsen som foretrukne alkanoylgrupper er acetyl, propi-nyl, butyryl og isobutyryl. Som foretrukne salte, hvor R3 er phosphono, kan nævnes alkalimetalsalte og ammoniumsalte eller substituterede ammoniumsalte, såsom natrium-, kalium- eller 35 ammoniumsaltet.Particular meanings of R *, R 2 and R 3 in the compounds of the invention as preferred alkanoyl groups are acetyl, propinyl, butyryl and isobutyryl. As preferred salts where R 3 is phosphono may be mentioned alkali metal salts and ammonium salts or substituted ammonium salts such as the sodium, potassium or ammonium salt.
Når Ri og R2 begge er H, er R3 fortrinsvis H, Cj.Cø-alkanoy1, DK 16776b ΒΊ 5 4 ΟWhen R 1 and R 2 are both H, R 3 is preferably H, C 2 -C 8 alkanoyl, DK 16776b ΒΊ 5 4 Ο
IIII
eller ΗΟ-Ρ-, og når R1 og R2 begge er Ci-Cø-alkanoy1, er R3 OHor ΗΟ-Ρ-, and when R 1 and R 2 are both C 1 -C 8 alkanoyl, R 3 is OH
Ci-Cg-alkanoyl.Ci-Cg alkanoyl.
Farmaceutisk midler indeholdende de ved fremgangsmåden ifølge opfindelsen fremstillede forbindelser kan fremstilles på enhver egnet måde, fortrinsvis sammen med en indifferent bærer. 10 Den farmaceutisk bærer vælges fortrinsvis til at muliggøre administration af en passende koncentration af midlet som en opløsning eller suspension ved indsprøjtning i et angrebet varmblodet dyr. Afhængigt af værten, der huser den ondartede svulst, svulsttypen samt svulstens sted, eller, afhængigt af 15 den virale infektion og infektionstype og infektionens sted, som tilfældet kan være, kan administrationen ved hjælp af indsprøjtning være intravenøs, intramuskulær, intracerebral, subkutan eller intraperitoneal.Pharmaceutical agents containing the compounds of the present invention can be prepared in any suitable manner, preferably together with an inert carrier. The pharmaceutical carrier is preferably selected to allow the administration of a suitable concentration of the agent as a solution or suspension by injection into an infected warm blooded animal. Depending on the host that houses the malignant tumor, the type of tumor and the site of the tumor, or, depending on the viral infection and infection type and site of infection, the administration by injection may be intravenous, intramuscular, intracerebral, subcutaneous or intraperitoneal. .
2020
Alternativt kan midlet sammensættes med en passende farmaceutisk bærer, der muliggør administration ad en anden vej, såsom oral, ophthalmisk, topisk eller som suppositorie.Alternatively, the agent may be formulated with a suitable pharmaceutical carrier which enables administration by another route, such as oral, ophthalmic, topical or as a suppository.
Alkanoylgrupperne kan vælges blandt ligekædede, forgrenede, 25 substituerede, umættede, mættede eller aromatiske syrer, såsom, men ikke nødvendigvis begrænset til, eddikesyre, triflu-oreddikesyre, propionsyre, n-smørsyre, isosmørsyre, valerianesyre, capronsyre, pelargonsyre, ønantsyre, palmi tinsyre, benzoesyre, phthalsyre, salicylsyre, kanelsyre og naphthalencar-30 boxylsyre. Med hensyn til phosphatforbindelser, der er fremstillet ved fremgangsmåden ifølge opfindelsen, kan phospho-rylesteren foreligge som en fri syre eller i saltform. Acceptable salte af phosphatdelen kan vælges fra, men er ikke nødvendigvis begrænset til, en gruppe bestående af alkali- og 35 jordalkalimetaller, f.eks. natrium, kalium, calcium, magnesium og lithium, ammonium og substitueret ammonium omfattende trialkylammonium, dialkylammonium og allylammonium, f.eks.The alkanoyl groups may be selected from straight-chain, branched, substituted, unsaturated, saturated or aromatic acids such as, but not necessarily limited to, acetic acid, trifluoroacetic acid, propionic acid, n-butyric acid, isobutyric acid, valeric acid, capric acid, pelargonic acid, pelargonic acid, , benzoic acid, phthalic acid, salicylic acid, cinnamic acid and naphthalene carboxylic acid. In the case of phosphate compounds prepared by the process of the invention, the phosphoryl ester may be present as a free acid or in salt form. Acceptable salts of the phosphate moiety may be selected from, but not necessarily limited to, a group consisting of alkali and alkaline earth metals, e.g. sodium, potassium, calcium, magnesium and lithium, ammonium and substituted ammonium comprising trialkylammonium, dialkylammonium and allylammonium, e.g.
DK 167765 B1 5 triethylammonium, trimethylammonium, diethylammonium, octyl-ammonium og cetyltrimethylammonium samt cetylpyridinium.DK 167765 B1 5 triethylammonium, trimethylammonium, diethylammonium, octylammonium and cetyltrimethylammonium and cetylpyridinium.
Fremgangsmåden ifølge opfindelsen er kendetegnet ved, at man: 5 a) underkaster et alkyl-2-(2,3,5-tri-0-acyl-/3-D-ribofurano-syl)selenazol-4-carboxylat ammonolyse, b) phosphory1 erer 2-0-D-ribofuranosylselenazol-4-carboxamid, 10 c) acylerer 2-0-D-ribofuranosy 1 selenazol-4-carboxamid, og isolerer produktet, eventuelt i form af et salt.The process of the invention is characterized by: a) subjecting an alkyl 2- (2,3,5-tri-O-acyl- / 3-D-ribofuranosyl) selenazole-4-carboxylate ammonolysis; b) phosphorylates 2-O-D-ribofuranosylselenazole-4-carboxamide, c) acylates 2-O-D-ribofuranosyl-1-selenazole-4-carboxamide, and isolates the product, optionally in the form of a salt.
15 Ammonolysereaktionen til fremstilling af 2-/3-D-ribofuranosyl-selenazol-4-carboxamid (forbindelse 1) udføres i et passende opløsningsmiddel, såsom methanol. Reaktionsbeti.ngelserne kan varieres, såsom f.eks. ved omgivelsernes temperatur og tryk, fortrinsvis ved stuetemperatur, indtil reaktionen er afslut-20 tet, f.eks. i ca. 24 timer. Produktet isoleres fra reaktionsblandingen på en hvilken som helst egnet måde, såsom ved hjælp af søjlekromatografi. Udgangsmaterialets alkyl- og acylgrup-per kan varieres inden for vide grænser, eftersom de fjernes under reaktionen, og valget deraf er således ikke kritisk. Fo-25 retrukne alkylgrupper er C^-Cg-alkylgrupper. Foretrukne acyl-grupper er acetylgruppen, n-butyrylgruppen og benzoylgruppen.The ammonolysis reaction to prepare 2- / 3-D-ribofuranosyl-selenazole-4-carboxamide (Compound 1) is carried out in a suitable solvent such as methanol. The reaction conditions can be varied, such as e.g. at ambient temperature and pressure, preferably at room temperature, until the reaction is complete, e.g. for approx. 24 hours. The product is isolated from the reaction mixture in any suitable manner, such as by column chromatography. The alkyl and acyl groups of the starting material can be varied within wide limits since they are removed during the reaction and the choice thereof is thus not critical. Preferred alkyl groups are C 1 -C 6 alkyl groups. Preferred acyl groups are the acetyl group, the n-butyryl group and the benzoyl group.
Phosphoryleringsreaktionen til fremstilling af 2-p-D-ribofu-ranosylselenazol-4-carboxamid-5'-phosphatforbindelserne ud- 30 føres roed den nævnte forbindelse 1 samt et phosphorylerings-middel, såsom phosphorylchlorid, fordelagtigt i kulden, i et passende medium, såsom triethylphosphat eller pyridin og ace-tonitril. Produktet isoleres fra reaktionsblandingen på en hvilken som helst egnet måde, såsom ved ionbytningskromatogra-35 fi. Acylering udføres ved omsætning af forbindelsen 1 med acy-leringsmidlet, såsom et syreanhydrid eller syrechlorid, fortrinsvis i overskud ved omgivelsernes temperatur, indtil reaktionen er afsluttet.The phosphorylation reaction to prepare the 2-pD-ribofuranosyl selenazole-4-carboxamide-5'-phosphate compounds is carried out by said compound 1 and a phosphorylating agent such as phosphoryl chloride, advantageously in the cold, in a suitable medium such as triethyl phosphate or pyridine and acetonitrile. The product is isolated from the reaction mixture in any suitable manner, such as by ion exchange chromatography. Acylation is carried out by reacting compound 1 with the acylating agent, such as an acid anhydride or acid chloride, preferably in excess at ambient temperature until the reaction is complete.
Ulv ΙΟ/ /Οϋ D IWolf ΙΟ / / Οϋ D I
66
Opfindelsen og den bedste måde at udøve den på beskrives i de følgende eksempler.The invention and the best way to practice it are described in the following examples.
Eksempel 1 SExample 1 S.
2-jJ-D-ribofuranosylselenazol-4-carboxamid, forbindelse 1 2,5-anhydro-3,4,6-tri-O-benzoyl-D-al1 onselenocarboxamid.2-β-D-ribofuranosylselenazole-4-carboxamide, Compound 1 2,5-anhydro-3,4,6-tri-O-benzoyl-D-alzeneselenocarboxamide.
a) En blanding af 2,3,5-tri-0-benzoyl-8-P“ribofuranosyl= 10 cyanid (10,Og, 21,2 mmol), 4-axmethylaminopyridin (200 mg) og flydende hydrogenselenid (kondenseret under en atmosfære, 20 ml) blev omrørt i en lukket bombe ved stuetemperatur i 20 timer. Hydrogenselenid fik lov til at afdampe. Den mørkt farvede rest blev opløst i chloroform 15 (200 ml) og vasket i rækkefølge med vand (3 x 50 ml) , mættet NaHCO^ (3 x 50 ml) efterfulgt af vand (2 x 50 ml) . Chloroformportionen blev tørret (MgSO^) og under vakuum inddampet til opnåelse af produktet med undertitlen som et skum i næsten kvantitativt udbytte. Sidstnævnte pro-20 dukt med analyserenhed blev opnået ved hjælp af søjlekromatografi (silicagel, 5% ethylacetat i chloroform).a) A mixture of 2,3,5-tri-O-benzoyl-8-P-ribofuranosyl = 10 cyanide (10, and, 21.2 mmol), 4-axmethylaminopyridine (200 mg) and liquid hydrogen selenide (condensed under a atmosphere, 20 ml) was stirred in a closed bomb at room temperature for 20 hours. Hydrogen selenide was allowed to evaporate. The dark colored residue was dissolved in chloroform 15 (200 ml) and washed successively with water (3 x 50 ml), saturated NaHCO 3 (3 x 50 ml) followed by water (2 x 50 ml). The chloroform portion was dried (MgSO4) and evaporated in vacuo to give the subtitle product as a foam in almost quantitative yield. The latter product with analyzer unit was obtained by column chromatography (silica gel, 5% ethyl acetate in chloroform).
Produktet udviklede en violet farve, når silicagelkroma-togrammet af produktet blev sprøjtet med en fortyndet etha= 25 nolopløsning af 2,3-dichlornaphthoquinon og blev udsat for ammoniak. Analyse beregnet for C2-7^23^0-780: C 58,91; H 4,21; Se 13,98. Fundet: C 58,81; H 4,29; N 2,51; Se 13,74.The product developed a violet color when the silica gel chromatogram of the product was sprayed with a dilute etha = 25 nol solution of 2,3-dichloro naphthoquinone and exposed to ammonia. Analysis calculated for C2-7C23-780: C 58.91; H, 4.21; See 13.98. Found: C, 58.81; H, 4.29; N, 2.51; See 13.74.
Omsætning af 2,5-anhydro-3,4,6-tri-0-benzoyl-D-allonseleno-3 0 carboxamid med ethylbrompyruvat samt syntese af ethyl-2-(2,3,5-tri-o-benzoyl-D-ribofuranosyl)selenazol-4-carboxy= later.Reaction of 2,5-anhydro-3,4,6-tri-O-benzoyl-D-allone seleno-30-carboxamide with ethyl bromo-pyruvate and synthesis of ethyl 2- (2,3,5-tri-o-benzoyl-D (ribofuranosyl) selenazole-4-carboxy = later.
b) En opløsning af 2,5-anhydro-3,4,6-tri-O-benzoyl-D-3 5 allonselenocarboxamid (5,5 g, 10 mmol) i acetonitril (60 ml) blev kølet i is. Ethylbrompyruvat (3,0 g) i acetoni= tril (20 ml) blev dråbevis tilsat (10 minutter) . Isbadet DK 167765 B1 7 blev fjernet, og reaktionsblandingen blev omrørt ved stuetemperatur i 1 time- Opløsningsmidlet blev afdampet i vakuum, og resten blev findelt med en mættet natriumbi= carbonatopløsning (100 ml) samt ekstraheret med ethyl= 5 ether (2 x 100 ml). Den kombinerede etherportion blev vasket med vand og tørret (MgSO^). Etheren blev afdampet i vakuum og resten (sirup) ført gennem en silicagelsøjle (300 g), indeholdt i chloroform. Eluering med 5% ethyl= acetat i chloroform resulterede i produkter med under-10 titlen: nemlig det hurtigt bevægende ethyl-2(2,3,5-tri-0-benzoyl-2-B-D-ribofuranosyl)selenazol—4-carboxylat (2,5 g) og det langsomt bevægende ethyl-2-(2,3,5-tri-O-benzoyl-2-ct-D-ribofuranosyl) selenazol—4-carboxylat (1,0 g), der blev isoleret efter inddampning under formindsket 15 tryk i form af tyktflydende sirupper, β-isomeren, ethyl-2-(2,3,5-tri-0-benzoyl-2-p-D-ribofuranosyl)selenazol-4-carboxylat, er karakteriseret ved en optisk drejning, 1,07% i methanol, [α]ρ5 = 34,7°. Analyse beregnet for C32H27NOgSe (648,51): C 59,26; H 4,20; N 2,16. Fundet: C 59,44; 20 H 4,21; N 1,89.b) A solution of 2,5-anhydro-3,4,6-tri-O-benzoyl-D-35 allone selenocarboxamide (5.5 g, 10 mmol) in acetonitrile (60 ml) was cooled in ice. Ethyl bromo-pyruvate (3.0 g) in acetone = tril (20 ml) was added dropwise (10 minutes). The ice bath DK 167765 B7 was removed and the reaction mixture was stirred at room temperature for 1 hour. The solvent was evaporated in vacuo and the residue was triturated with a saturated sodium bicarbonate solution (100 ml) and extracted with ethyl = 5 ether (2 x 100 ml). ). The combined ether portion was washed with water and dried (MgSO 4). The ether was evaporated in vacuo and the residue (syrup) passed through a silica gel column (300 g), contained in chloroform. Elution with 5% ethyl = acetate in chloroform resulted in products of the subtitle: namely the fast moving ethyl 2 (2,3,5-tri-O-benzoyl-2-BD-ribofuranosyl) selenazole-4-carboxylate ( 2.5 g) and the slow-moving ethyl 2- (2,3,5-tri-O-benzoyl-2-ct-D-ribofuranosyl) selenazole-4-carboxylate (1.0 g) isolated after evaporation under reduced pressure in the form of viscous syrups, the β-isomer, ethyl 2- (2,3,5-tri-O-benzoyl-2-pD-ribofuranosyl) selenazole-4-carboxylate, is characterized by an optical rotation , 1.07% in methanol, [α] ρ5 = 34.7 °. Analysis calculated for C 32 H 27 NO 2 Se (648.51): C 59.26; H, 4.20; N, 2.16. Found: C, 59.44; H, 4.21; N, 1.89.
Forbindelse 1.Compound 1.
c) Ethyl-2-(2,3,5-tri-O-benzoyl-B-D-ribofuranosyl)se= 25 lenazol-4-carboxylat (3,2 g, 5 mmol) blev opløst i me= thanol (100 ml), kølet samt mættet med ammoniak (0°C). Opløsningen blev omrørt i en trykflaske ved stuetemperatur i 48 timer. Opløsningsmidlet blev afdampet i vakuum, og resten blev ekstraheret med chloroform (3 x 25 ml) .c) Ethyl 2- (2,3,5-tri-O-benzoyl-BD-ribofuranosyl) se = lenazole-4-carboxylate (3.2 g, 5 mmol) was dissolved in methanol (100 ml) , chilled and saturated with ammonia (0 ° C). The solution was stirred in a pressure flask at room temperature for 48 hours. The solvent was evaporated in vacuo and the residue was extracted with chloroform (3 x 25 ml).
30 Chloroformmængden blev bortkastet. Resten blev adsorberet på silicagel (10 g) ved hjælp af methanol og påført på en silicagelsøjle (2,8 x 45 cm), indeholdt i ethylacetat. Søjlen blev elueret med opløsningsmiddel E (ethylacetat, n-propanol, H20; 4:1:2; vol./vol.: øverste lag danner 35 opløsningsmiddel E), og de homogene fraktioner (Rf = 0,42, silicagel-tlc i opløsningsmiddel E) indeholdende hovedproduktet blev opsamlet. Opløsningsmidlet blev afdampetThe amount of chloroform was discarded. The residue was adsorbed on silica gel (10 g) by methanol and applied to a silica gel column (2.8 x 45 cm) contained in ethyl acetate. The column was eluted with solvent E (ethyl acetate, n-propanol, H 2 O; 4: 1: 2; v / v: upper layer forming solvent E) and the homogeneous fractions (R f = 0.42, silica gel-tlc solvent E) containing the main product was collected. The solvent was evaporated
UK lb//oo D IUK lb // oo D I
8 i vakuum, og titelforbindelsen blev som rest krystalliseret fra 2-propanol: udbytte 900 mg af titelforbindelsen, forbindelse 1, (60%), med smeltepunkt 135 - 136°C. Resten resulterede i et andet udbytte (200 mg) med smeltepunkt 5 131 - 133°C. Analyse beregnet for cgHi2N2°5Se: C 35,19; H 3,94; N 9,12; Se 25,71- Fundet: C 35,43; H 3,97; N 9,03;8 in vacuo, and the title compound was crystallized as residue from 2-propanol: yield 900 mg of the title compound, compound 1, (60%), mp 135-136 ° C. The residue resulted in another yield (200 mg), mp 5 131-133 ° C. Analysis calculated for cg H 2 N 2 O 5 Se: C 35.19; H, 3.94; N, 9.12; See 25.71- Found: C, 35.43; H, 3.97; N, 9.03;
Se 25,55. [a]^5 , 1,07% i methanol, -22,2°. LD10, akut toksicitet, 96,5 mg/kg ved intraperitoneal injektion i mus.See 25.55. [.alpha.] @ 5, 1.07% in methanol, -22.2 °. LD10, acute toxicity, 96.5 mg / kg by intraperitoneal injection in mice.
10 Eksempel 2 2-/S-D-ribof uranosylselenazol -4-carboxamid-5' -phosphat, forbindelse 2.Example 2 2- / S-D-ribofuranosylselenazole -4-carboxamide-5 'phosphate, compound 2.
15 Vand (151 mg, 8,4 mmol) blev forsigtigt sat til en opløsning (holdt ved 0°C ved hjælp af omrøring) af phosphoryl= chlorid (2,0 g, 13,2 mmol), pyridin (1,21 g, 14,4 mmol) og acetonitril (2,3 g, 56,7 mmol). 2-8-D-ribofuranosyl= selenazol-4-carboxamid (921· mg, 3,0 mmol) blev sat til op-20 løsningen, og reaktionsblandingen omrørtes i 4 timer ved 0°C. En klar opløsning opnåedes, og denne blev udhældt i isvand (50 ml), hvorefter pH-værdien blev indstillet til 2,0 med koncentreret natriumhydroxid. Opløsningen blev påført på en søjle af aktivt carbon (30 g), og søjlen 2 5 blev vasket grundigt med vand, indtil eluatet var saltfrit. Søjlen blev elueret med en opløsning af ethanol/ vand/koncentreret ammoniumhydroxid (10:10:1), og fraktionerne (hver på 25 ml) blev opsamlet. Fraktionerne indeholdende nucleotidtitelforbindelsen, forbindelse 2, i 30 ren form (tic, silicagel, acetonitril-0,1 N ammonium= chlorid (7:3)) blev opsamlet og inddampet til tørhed under vakuum. Det vandfri restprodukt, forbindelse 2, blev opløst i vand og ført gennem en søjle af "Dowex" 50W- X8 (20 - 50 mesh, H+-form, 15 ml)- Søjlen blev vasket 3 5 med vand, og fraktionen indeholdende nucleotidet blev opsamlet. Opløsningen blev inddampet til et ringe volumen (5 ml) og ført gennem en søjle af "Dowex" 50W-X8 (20 - DK 167765 B1 9 50 mesh, Na+-form, 15 ml) . Søjlen blev vasket med vand. Fraktionen indeholdende nucleotidet i form af natriumsaltet blev lyofiliseret. Resten blev findelt med etha= nol, opsamlet ved hjælp af filtrering samt tørret (P205) 5 til opnåelse af 580 mg (42%) 2-|3-D-ribofuranosylselena= zol-4-carboxamid-5'-phosphat som mononatriumtrihydrat i den krystallinske form. Analyse beregnet for C9Hi2N2°8= PSeNa,3H20: C 23,33; H 3,90; N 6,05; P 6,69; Se 17,04.Water (151 mg, 8.4 mmol) was carefully added to a solution (maintained at 0 ° C by stirring) of phosphoryl = chloride (2.0 g, 13.2 mmol), pyridine (1.21 g , 14.4 mmol) and acetonitrile (2.3 g, 56.7 mmol). 2-8-D-ribofuranosyl = selenazole-4-carboxamide (921 · mg, 3.0 mmol) was added to the solution and the reaction mixture was stirred for 4 hours at 0 ° C. A clear solution was obtained and poured into ice-water (50 ml), after which the pH was adjusted to 2.0 with concentrated sodium hydroxide. The solution was applied to an active carbon column (30 g) and the column was thoroughly washed with water until the eluate was salt free. The column was eluted with a solution of ethanol / water / concentrated ammonium hydroxide (10: 10: 1) and the fractions (each of 25 ml) were collected. The fractions containing the nucleotide title compound, compound 2, in pure form (tic, silica gel, acetonitrile-0.1 N ammonium = chloride (7: 3)) were collected and evaporated to dryness under vacuum. The anhydrous residue, compound 2, was dissolved in water and passed through a column of "Dowex" 50W-X8 (20 - 50 mesh, H + form, 15 ml) - The column was washed with water and the fraction containing the nucleotide collected. The solution was evaporated to a small volume (5 ml) and passed through a column of "Dowex" 50W-X8 (20 - 50 mesh, Na + form, 15 ml). The column was washed with water. The fraction containing the nucleotide in the form of the sodium salt was lyophilized. The residue was triturated with ethanol, collected by filtration, and dried (P205) 5 to give 580 mg (42%) of 2- | 3-D-ribofuranosyl selenazole-4-carboxamide-5'-phosphate as monosodium trihydrate in the crystalline form. Analysis calculated for C 9 H 21 N 2 ° 8 = PSeNa, 3H 2 O: C, 23.33; H, 3.90; N, 6.05; P, 6.69; See 17.04.
Fundet: C 23,01; H 3,76; N 5,86; P 7,02; Se 16,32.Found: C, 23.01; H, 3.76; N, 5.86; P, 7.02; See 16.32.
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Eksempel 3 2-(2,3,5-tri-0-acetyl-0-D-ribofuranosyl)selenazol-4-carbox-amid, forbindelse 3.Example 3 2- (2,3,5-Tri-O-acetyl-O-D-ribofuranosyl) selenazole-4-carboxamide Compound 3.
1515
En blanding af 2-8-D-ribofuranosylselenazol-4-carboxamid (1,0 g, 3,25 mmol), Ν,Ν-dimethylaminopyridin (katalysator, 80 mg) og eddikesyreanhydrid (15 ml) blev omrørt ved stuetemperatur i 3 timer. Opløsningsmidlet blev afdampet 20 i vakuum og af dampet samtidigt med vand (2 x 10 ml) til opnåelse af forbindelse 3 som et hvidt, krystallinsk produkt, som blev findelt med vand og opsamlet ved hjælp af filtrering. Produktet blev rekrystalliseret fra vand indeholdende nogle få dråber ethanol til opnåelse af hvide 25 nåle i et udbytte på 1,2 g (85%) med smeltepunkt 117 -119°C. Analyse beregnet for c15H18N20gSe: C 41,58; H 4,19; N 6,47; Se 18,22. Fundet C 41,80; H 4,30; N 6,58;A mixture of 2-8-D-ribofuranosylselenazole-4-carboxamide (1.0 g, 3.25 mmol), Ν, Ν-dimethylaminopyridine (catalyst, 80 mg) and acetic anhydride (15 ml) was stirred at room temperature for 3 hours. . The solvent was evaporated in vacuo and evaporated simultaneously with water (2 x 10 ml) to give Compound 3 as a white crystalline product which was triturated with water and collected by filtration. The product was recrystallized from water containing a few drops of ethanol to give white 25 needles in a yield of 1.2 g (85%), mp 117-111 ° C. Analysis calculated for c15 H18 N2 O2 Se: C, 41.58; H, 4.19; N, 6.47; See 18.22. Found C 41.80; H, 4.30; N, 6.58;
Se 17,97. Tilsvarende 2',3',5'-0-acylforbindelser fremstilles ifølge opfindelsen ud fra forbindelse 1 ved hjælp af denne 30 procedure ved omsætning af sidstnævnte med det behørige syre-anhydrid, indtil reaktionen er afsluttet, og isolation af produktet i ren form. 1 10See 17.97. Corresponding 2 ', 3', 5'-0-acyl compounds of the invention are prepared from Compound 1 by this procedure by reacting the latter with the appropriate acid anhydride until the reaction is complete and isolating the product in pure form. 1 10
Som illustrerende eksempler på antisvulstanvendelsen af forbindelserne 1 og 2 anføres nedenfor eksemplerne 4 til 6. I disse eksempler demonstreres effektiviteten af forbindelserne ved anvendelse af standardforsøg over 5 for en ondartet svulst, Lewis' lungecarcinom. De i disse illustrative eksempler benyttede forsøg blev udført af the Developmental Therapeutics Program, Division of Cancer Treatment, National Cancer Institute. Forsøgene blev overvåget af dette foretagende under anvendelse af dettes standardforskrifter og procedurer. Alle forsøg blev udført i overensstemmelse med disse forskrifter, og alle forsøg blev bedømt i henhold til.de kriterier, der er defineret i henhold til disse forskrifter. De efterfølgende repræsentative eksempler illustrerer på 15 bekræftende made virkningen af de illustrative forbindelser ifølge opfindelsen over for sorterende svulstsystemer i henhold til the National Cancer Institute.Illustrative examples of the anti-tumor use of compounds 1 and 2 are given below Examples 4 to 6. These examples demonstrate the effectiveness of the compounds using standard experiments above 5 for a malignant tumor, Lewis's lung carcinoma. The experiments used in these illustrative examples were carried out by the Developmental Therapeutics Program, Division of Cancer Treatment, National Cancer Institute. The experiments were monitored by this undertaking using its standard regulations and procedures. All tests were performed in accordance with these regulations and all tests were evaluated according to the criteria defined under these regulations. The following representative examples illustrate in 15 affirmative action the illustrative compounds of the invention against sorting tumor systems according to the National Cancer Institute.
Til de følgende eksemplers formål står forkortelsen IPFor the purposes of the following examples, the abbreviation stands for IP
20 for intraperitoneal, og IV star for intravenøs. Middel- og medianoverlevelsestider er beregnet i instruktion 14 (revision 6/78) i the Screening Data Summary, Develop= mental Therapeutics Program, Division of Cancer Treatment,20 for intraperitoneal, and IV for intravenous. Mean and median survival times are calculated in instruction 14 (revision 6/78) of the Screening Data Summary, Develop = Mental Therapeutics Program, Division of Cancer Treatment,
National Cancer Institute. Indholdet af denne sorterings-25 datasaramenfatning inklusive tilsvarende revisioner medtages heri ved henvisningen dertil. 1 de nedenfor illustrerede eksempler blev den som bærer for lægemidlet benyttede grundmasse indsprøjtet (minus 30 noget lægemiddel deri) i kontroldyrene i den samme brugsmængde af grundmassen som til de lægemiddelbehandlede dyr med henblik på eliminering af enhver grundmas sevirkning ved forsøgene.National Cancer Institute. The contents of this sorting data summary, including corresponding revisions, are incorporated herein by reference. In the examples illustrated below, the carrier used for the drug was injected (minus 30 any drug therein) into the control animals in the same amount of use of the matrix as for the drug treated animals to eliminate any matrix effect in the experiments.
35 2-3-D-ribofuranosylselenazol-4-carboxamid, forbindelse 1, er anført som værende aktiv over for Lewis' lungecarci= nom ifølge eksempel 4 og opfyldte på vellykket måde DN (decision network) 2 kriterierne ifølge the National Cancer Institute Testing. Til eksempel 4' benyttedes BgD2Fl~ 112-3-D-ribofuranosylselenazole-4-carboxamide, Compound 1, is listed as active against Lewis lung cancer according to Example 4 and successfully met the DN (decision network) 2 criteria of the National Cancer Institute Testing. For example 4 ', BgD2F1 ~ 11 was used
UK 1b//bt> bTUK 1b // bt> bT
hanmus, som blev smittet med Lewis' lungecarcinom. Forsøgsdyrenes medianoverlevelsestid blev sammenlignet med medianoverlevelsestiden for tilsvarende kontroldyr. Baseret på dette kriterium blev forbindelse 1 betragtet 5 som et effektivt antisvulstmiddel.male mice that were infected with Lewis lung carcinoma. The median survival time of the test animals was compared to the median survival time of similar control animals. Based on this criterion, Compound 1 was considered to be an effective antifungal agent.
I eksempel 4 blev 40 kontroldyr og 10 forsøgsdyr benyttet, hvert dyr ved dosismængder anført nedenfor i tabel 1. Både i kontrolgruppen og i den lægemiddelbehandlede ^ gruppe blev svulster fremkaldt ved IV-injektion på dagen nul efterfulgt af begyndende lægemiddelbehandling på dagen 1. I eksempel 4 blev vand benyttet som grundmasse for lægemidlet.In Example 4, 40 control animals and 10 test animals were used, each animal at dose levels listed below in Table 1. Both in the control group and in the drug-treated group, tumors were induced by zero-day IV injection followed by starting drug treatment on day 1. In Example 4, water was used as the matrix for the drug.
15 I bade kontrolgruppen og den lægemiddelbehandlede gruppe i eksempel 4, blev dyrene på dagen nul podet med et g homogenat af 10 podeceller af Lewis' lungecarcinom. I eksempel 12 blev lægemiddelbehandling påbegyndt på dagen 1, og forbindelse 1 administreres én gang daqligt i 9 20 dage. Den 5. dag blev benyttet som skæringsdag for dødsfald, som kunne henføres til lægemidlets toksicitet. Der var i dette eksempel ingen dødelighed, som -måtte tilskrives lægemidlets toksicitet. Behandlingseffektivitet blev bestemt ved sammenligning af kontroldyrenes median-25 overlevelsestid, og den udtrykkes som procentisk forøgelse af behandlede dyr/kontroldyr (T/C).In both the control group and the drug-treated group of Example 4, the animals were zero seeded on the day with a g homogenate of 10 seed cells of Lewis lung carcinoma. In Example 12, drug treatment was started on day 1 and compound 1 was administered once daily for 9 days. The 5th day was used as the day of death, which was attributable to the drug's toxicity. In this example, there was no mortality attributable to the toxicity of the drug. Treatment efficacy was determined by comparing the median survival time of the control animals and it is expressed as percentage increase in treated animals / control animals (T / C).
Forsøgsperioden var 60 dage, og ved afslutningen af den 60 dages periode blev alle i forsøgsgrupperne overleven-30 de dyr bedømt som værende enten helbredte, ikke-modtagelige eller svulstoverlevere.The trial period was 60 days, and at the end of the 60-day period, all surviving animals in the experimental groups were rated as either cured, non-susceptible or tumor survivors.
Eksempel 4._ 35 I dette eksempel blev de lægemiddelafprøvede dyr injiceret IP med den i nedenstående tabel 1 anførte dosismængde.Example 4._ 35 In this example, the drug-tested animals were injected IP with the dose amount listed in Table 1 below.
10 dyr blev behandlet ved hver dosismængde. Ingen kontroldyr overlevede efter dag 23 med en mediandødsdatoTen animals were treated at each dose level. No control animals survived after day 23 with a median date of death
UK I0//00 D IUK I0 // 00 D I
1212
på dag 19,0. Ved dosismængder på 75 og 13 mg/kg overlevede alle de behandlede dyr, hvilket indebærer en T/C på 315% og henholdsvis 7 ud af 10 og 5 ud af 10 helbredelser. Ved den relativt lave dosis på 3 mg/kg blev endvidere 5 DN2-kriteriet ifølge NCI opfyldt ved opnåelse af en T/Con day 19.0. At dose levels of 75 and 13 mg / kg, all treated animals survived, implying a T / C of 315% and 7 out of 10 and 5 out of 10 cures, respectively. Furthermore, at the relatively low dose of 3 mg / kg, the 5 DN2 criterion according to NCI was met by obtaining a T / C
på 152%. 1 helbredelse blev opnået ved denne· dosismængde.of 152%. 1 cure was achieved at this dose.
Forbindelse 1 er anført som værende en aktiv antisvulst-forbindelse ved de anførte flerdosisundersøgelser.Compound 1 is listed as an active anti-tumor compound in the multidose studies listed.
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Tabel 1.Table 1.
Antisvulstvirkning - forbindelse 1.Anti-tumor effect - compound 1.
15 lægemiddel- Behandlet Kontrol Helbred- Procent dosis gruppe, gruppe, eiser behandlede mg/kg overlevelses- overlevelses- dyr/kontrol- tid - tid dyr.15 Drug-Treated Control Health- Percent dose group, group, claimant treated mg / kg survival-survival animal / control-time - time animals.
75 60,0 19,0 7/10 315% 20 50 18,0 1/10 94% 33 18,0 3/10 94% 20 16,0 2/10 13 60,0 5/10 315% 9 10,4 3/10 25 6 12,0 1/10 3 28,9 1/10 152%75 60.0 19.0 7/10 315% 20 50 18.0 1/10 94% 33 18.0 3/10 94% 20 16.0 2/10 13 60.0 5/10 315% 9 10, 4 3/10 25 6 12.0 1/10 3 28.9 1/10 152%
Som vist i tabel 1 udviser forbindelse 1 fremragende virkning mod Lewis' lungecarcinom. Lewis' lungecarcinom 3 0 er et fortrinligt eksempel på et metastatisk svulstsystem. Forsøgsdyrene og kontroldyrene blev i eksempel 12 podet IV med et homogenat af svulsten. Dramatisk ekspression af denne svulst ses derefter i lungerne. Evnen til metastasedannelse er en egenskab, der specielt karakteri-3 5 serer en ondartet svulst i forhold til en godartet svulst.As shown in Table 1, Compound 1 exhibits excellent efficacy against Lewis lung carcinoma. Lewis's lung carcinoma 30 is a prime example of a metastatic tumor system. The test animals and control animals were inoculated in Example 12 with a homogenate of the tumor. Dramatic expression of this tumor is then seen in the lungs. The ability of metastasis formation is a feature that specifically characterizes a malignant tumor compared to a benign tumor.
DK 167765 B1 13DK 167765 B1 13
Eksempel ·5.Example · 5.
I dette eksempel blev forbindelse 1 afprøvet i BrD„F,-hunmus, der blev smittet med Lewis’ lungecarcinom. Me-5 dianoverlevelsestiden for forsøgsdyrene blev sammenlig net med medianoverlevelsestiden for tilsvarende kontroldyr· På basis af dette kriterium viste forbindelse 1 sig at være et effektivt antisvulstmiddel som vist i tabel 2. Ved dosismængder på 50, 25 og 12,50 mg/kg overlevede alle forsøgsdyrene, hvilket fører til en T/C på 355%.In this example, compound 1 was tested in BrD "F" females infected with Lewis lung carcinoma. The median survival time of the test animals was compared to the median survival time of the corresponding control animal · On the basis of this criterion, compound 1 proved to be an effective anti-swelling agent as shown in Table 2. At dose levels of 50, 25 and 12.50 mg / kg, all survived the test animals, leading to a T / C of 355%.
Henholdsvis 6 ud af 10, 7 ud af 10 og 8 ud af 10 helbredelser blev opnået.6 out of 10, 7 out of 10 and 8 out of 10 cures were respectively obtained.
15 Tabel 2.Table 2.
Antisvulstvirkning - forbindelse-1.Anti-tumor effect - compound-1.
Lægemiddel- Behandlet Kontrol Helbred- Procent 20 dosis gruppe, gruppe, eiser behandlede rogAg overlevelses- overlevelses- dyr/kontrol- tid tid dyr.Drug-Treated Control Health- Percent 20 dose group, group, claimant treated rogAg survivor survival animal / control time animal.
200 10,7 16,9 0/10 25 100 20/3 3/10 120 50 60,0 6/10 355 25 60,0 7/10 355 12 60,0 8/10 355200 10.7 16.9 0/10 25 100 20/3 3/10 120 50 60.0 6/10 355 25 60.0 7/10 355 12 60.0 8/10 355
Forbindelse 1 blev yderligere afprøvet i en Lewis' lunge 30 , , xn vivo musemodel under anvendelse af B^D^F,-hunmus, der O 2 1 blev smittet med Lewis' lungecarcinom. Resultaterne er anført i tabel 3. Som vist fører forbindelse 1 i lave dosismængder (24, 12 og 6 mg/kg) til en T/C på 297%.Compound 1 was further tested in a Lewis lung 30, xn vivo mouse model using B ^ D ^ F, female mice that were infected with Lewis lung carcinoma. The results are listed in Table 3. As shown, compound 1 in low dose amounts (24, 12 and 6 mg / kg) leads to a T / C of 297%.
Henholdsvis 9 ud af 10, 9 ud af 10 og 5 ud af 10 hel-35 bredeiser blev opnået. Forbindelse 1 frembragte en DN2-virkningsgrad (procent T/C større end 150) på 153 ved den lave dosis på 3 mg/kg. Resultaterne bekræfter, at forbindelse 1 er et effektivt antisvulstmiddel over for Lewis' lungecarcinom hos mus.9 out of 10, 9 out of 10 and 5 out of 10 complete 35 degrees were respectively obtained. Compound 1 produced a DN2 efficiency (percent T / C greater than 150) of 153 at the low dose of 3 mg / kg. The results confirm that Compound 1 is an effective antifungal agent for Lewis lung carcinoma in mice.
1414
Antisvulstvirkning - forbindelse 1.Anti-tumor effect - compound 1.
5 DK 167765 B15 DK 167765 B1
Tabel 3.Table 3.
Lægemiddel- Behandlet ’ Kontrol Helbred- Procent dosis gruppe, gruppe, eiser behandlede iaq/kq overlevelses- overlevelses- dyrAontrol- tid tid dyr.Drug-Treated 'Control Health- Percentage dose group, group, claimant treated iaq / kq survival-survival animal Control-time animal.
10 _*_ 24.00 60,0 20,2 9/10 297 12.00 60,0 9/10 297 6.00 60,0 5/10 297 3.00 31,0 0/10 153 15 1,50 22,3 0/10 110 0,75 21,7 0/10 10710 _ * _ 24.00 60.0 20.2 9/10 297 12.00 60.0 9/10 297 6.00 60.0 5/10 297 3.00 31.0 0/10 153 15 1.50 22.3 0/10 110 0.75 21.7 0/10 107
Eksempel 6 20Example 6 20
Forbindelse 2, 2- (5-phosphono-f3-D-ribofuranosyl) selena= zol-4-carboxamid, blev afprøvet for virkning mod Lewis' lungecarcinom på en måde svarende til den i eksempel 4 beskrevne. I dette eksempel blev B6D2Fl-hanmus smittet med Lewis' lungecarcinom. Middeloverlevelsestiden for 25 forsøgsdyrene blev sammenlignet med middeloverlevelsestiden for tilsvarende kontroldyr. På basis af dette kriterium blev forbindelse 2 betragtet som et effektivt anti-' svulstmiddel. I dette eksempel opnåedes helbredelser gående fra 1 ud af 10 til 4 ud af 10 ved en dosis gående fra 30 9 mg/kg til 75 mg/kg som vist i nedenstående tabel 4.Compound 2, 2- (5-phosphono-β-D-ribofuranosyl) selenazole-4-carboxamide was tested for efficacy against Lewis lung carcinoma in a manner similar to that described in Example 4. In this example, male B6D2F1 mice were infected with Lewis lung carcinoma. The mean survival time of the 25 test animals was compared to the mean survival time of similar control animals. On the basis of this criterion, compound 2 was considered an effective anti-tumor agent. In this example, cures ranging from 1 in 10 to 4 in 10 were obtained at a dose ranging from 30 9 mg / kg to 75 mg / kg as shown in Table 4 below.
Ved 13 mg/kg har de behandlede, overlevende mus en T/C på 315%, og 4 ud af 20 helbredelser blev opnået.At 13 mg / kg, the treated surviving mice have a T / C of 315% and 4 out of 20 cures were achieved.
3535
Antisvulstvirkning - forbindelse 2.Anti-tumor effect - compound 2.
DK 167765 Bl 15DK 167765 Pg 15
Tabel 4.Table 4.
5 Lægemiddel- Behandlet Kontrol Helbred- Procent dosis gruppe, gruppe, eiser behandlede mgAg overlevelses- overlevelses- dyrAontrol- tid tid dyr.5 Drug-Treated Control Health- Percent dose group, group, claimant treated mgAg survivor survivor animalsControl time animals.
75 15,5 19,0 1/10 10 50 12,5 3/10 33 12,5 3/10 20 12,0 2/10 13 60,0 4/10 315 9 12,5 1/10 15 6 22,0 0/10 115 3 20,8 0/10 10975 15.5 19.0 1/10 10 50 12.5 3/10 33 12.5 3/10 20 12.0 2/10 13 60.0 4/10 315 9 12.5 1/10 15 6 22 , 0 0/10 115 3 20.8 0/10 109
Ved yderligere forsøg blev vækstinhiberende virkninger af forbindelse 1 og forbindelse 2 målt over for 3 muse-20 svulstslægter i suspensionscellekultur. Cellekulturer blev initieret ved en tæthed på 50.000 celler/mg i mediet.' RPftE 1630 suppleret med 10% kalvefosterserum. Sammensætningen af dette kulturmedium og detaljer ved dyrkningsproceduren fulgte den publiserede metode (G. E.In further experiments, growth inhibitory effects of Compound 1 and Compound 2 were measured against 3 mouse 20 genera in suspension cell culture. Cell cultures were initiated at a density of 50,000 cells / mg in the medium. RPftE 1630 supplemented with 10% fetal calf serum. The composition of this culture medium and details of the culture procedure followed the published method (G. E.
25 Morre, A. A. Sandberg og K. Ulrich, Suspension Cell25 Morre, A. A. Sandberg, and K. Ulrich, Suspension Cell
Culture and in vivo and in-vitro chromosome constitution of mouse leukemia L1210, Journal of the National Cancer Institute _36, 405-415, 1966) . Kulturer blev holdt ved 37 C i stationær suspensionskultur under en atmosfære 30 af 95% luft + 5% C02· Forsøgsforbindelser blev sat til behandlede kulturer på initieringstidspunktet og var kontinuerligt til stede. Efter 72 timer blev 40 ganges fortyndelser af lægemiddelbehandlede og ubehandlede kontrolkulturer fremstillet i 0,9% NACl-opløsning, og cel-35 ler blev talt med en elektronisk partikeltæller. Resul taterne ved forsøgene er vist i nedenstående tabel 5.Culture and in vivo and in vitro chromosome constitution of mouse leukemia L1210, Journal of the National Cancer Institute _36, 405-415, 1966). Cultures were maintained at 37 ° C in stationary suspension culture under an atmosphere 30 of 95% air + 5% CO 2 · Experimental compounds were added to treated cultures at the time of initiation and were continuously present. After 72 hours, 40-fold dilutions of drug-treated and untreated control cultures were prepared in 0.9% NACl solution, and cells were counted with an electronic particle counter. The results of the experiments are shown in Table 5 below.
De vækstinhiberende virkninger er udtrykt som IDgQ-værdier, nemlig inhiberende doser eller koncentrationer af forsøgsforbindelse, der kræves til formindskelse af celleop- DK 167765 Bl 16 tællingen i behandlede kulturer til 50% af celleoptællingen i ubehandlede kontrolkulturer.The growth inhibitory effects are expressed as IDgQ values, namely inhibitory doses or test compound concentrations required to decrease cell count in treated cultures to 50% of cell count in untreated control cultures.
Tabel 5.Table 5.
ID^q-værdier (molær) over for forskellige svulstcelleslægter .ID ^ q values (molar) against different tumor cell lineages.
L-1210 P388 B^gMelanomL-1210 P388 B ^ gMelanoma
Forbindelse 1 4,0 x 10~7 2,7 x 10~7 3,5 x ΙΟ-6Compound 1 4.0 x 10 ~ 7 2.7 x 10 ~ 7 3.5 x ΙΟ-6
Forbindelse 2 5,8 x lo"8 6,6 x 10~8 7,5 x 10"6Compound 2 5.8 x 10 "8 6.6 x 10 ~ 8 7.5 x 10" 6
Disse resultater viser, at forbindelse 1 og forbindelse 5 2 begge inhiberer vækst i cellekulturer af repræsentative svulstslægter i ekstrem lav dosis. I denne henseende viser 51-phosphatet (forbindelse 2) sig at være overlegent i forhold til forbindelse 1«These results show that Compound 1 and Compound 5 2 both inhibit cell culture growth of representative low-dose tumor genera. In this regard, the 51-phosphate (compound 2) is found to be superior to compound 1 '
Eksempel 7 10 I én udførelsesform udviste forbindelse 1 virkning over for både små og store vira af både DNA- KNA-typer ved virusbedømmelsesmetoden (VR) ifølge Sidwell et al., Appl. Microbiol. 22, 797 (1971). En virusbedømmelse, der er større end 1,0, angiver bestemt antiviral virkning. En 15 virusbedømmelse på 0,5 - 0,9 angiver moderat antiviral virkning, og en virusbedømmelse på mindre end 0,5 antyder ringe eller ingen tilsyneladende antiviral virkning. De nedenfor anførte resultater blev opnået ved afprøvning på "Microtest" II (Falcon Plastics) plastplader 20 med et monolag af Vero- eller HeLa-celler.Example 7 10 In one embodiment, Compound 1 exhibited activity against both small and large viruses of both DNA KNA types by the virus assessment method (VR) of Sidwell et al., Appl. Microbiol. 22, 797 (1971). A virus rating greater than 1.0 indicates a definite antiviral effect. A virus rating of 0.5 - 0.9 indicates moderate antiviral activity and a virus rating of less than 0.5 indicates little or no apparent antiviral effect. The results set forth below were obtained by testing on "Microtest" II (Falcon Plastics) plastic sheets 20 with a monolayer of Vero or HeLa cells.
Antiviral virkning af forbindelse 1.Antiviral effect of compound 1.
DK 167765 B1 17DK 167765 B1 17
Virusbe- ED^q (yg/ml) dønmelseVirus ED (q / µg / ml) dosing
Virus Vero HeLa Vero HeLa ENA-vira.Virus Vero HeLa Vero HeLa ENA viruses.
Para 3 2,6 2,2 1 1 Mæslinger 2,0 1,8 1 2 Fåresyge 1,7 1,0 5 1Para 3 2.6 2.2 1 1 Measles 2.0 1.8 1 2 Sheep disease 1.7 1.0 5 1
Eeo 3 1,8 2,7 1 8 VSV 0,4 2,1 1000 9Eeo 3 1.8 2.7 1 8 VSV 0.4 2.1 1000 9
Cox Bl 1,7 1,8 15 10Cox Bl 1.7 1.8 15 10
Cox B4 0,0 2,3 1000 6.Cox B4 0.0 2.3 1000 6.
DM-vira.DM viruses.
W 2,1 2,4 3 2W 2.1 2.4 3 2
Ad-2 1,9 9 HSV-1 1,2 1,4 30 2 HSV-2 1,5 1,5 10 4Ad-2 1.9 9 HSV-1 1.2 1.4 30 2 HSV-2 1.5 1.5 10 4
Resultaterne viser, at forbindelse 1 har en god bredspektret antiviral virkning over for både DNA- og RNA-vira. Af DNA-viraene blev repræsentanterne for familierne 5 Poxviridae (Vaccinia) og Herpesviridae (HSV-1, HSV-2) inhiberet mest. Størst virkning blev iagttaget over for repræsentanterne for KNA-familierne Paramyxoviridae (para-3, fåresyge, mæslinger) og Reoviridae (Reo-3). Fortrinlig antiviral virkning blev målt i HeLa-celler for 10 familierne Adenoviridae (Adeno-2), Picornaviridae (Cox Bl, Cox B4) og Rhabdoviridae (VSV).The results show that compound 1 has a good broad-spectrum antiviral effect against both DNA and RNA viruses. Of the DNA viruses, the representatives of the families 5 Poxviridae (Vaccinia) and Herpesviridae (HSV-1, HSV-2) were most inhibited. The greatest effect was observed against the representatives of the KNA families Paramyxoviridae (para-3, mumps, measles) and Reoviridae (Reo-3). Superior antiviral activity was measured in HeLa cells for the 10 families of Adenoviridae (Adeno-2), Picornaviridae (Cox B1, Cox B4) and Rhabdoviridae (VSV).
Undersøgelserne viser yderligere, at antiviral virkning af forbindelse 1 er både virusidal (over for Vaccinia)The studies further show that antiviral action of compound 1 is both viral (against Vaccinia)
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US36096882A | 1982-03-23 | 1982-03-23 | |
US36096882 | 1982-03-23 | ||
US06/465,221 US4531001A (en) | 1982-03-23 | 1983-02-15 | 2-β-D-ribofuranosylselenazole-4-carboxamide compounds |
US46522183 | 1983-02-15 |
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DK025093A DK172165B1 (en) | 1982-03-23 | 1993-03-08 | Intermediates for the preparation of therapeutically active 2-beta-D-ribofuranosylselenazole-4-carboxamide compounds |
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CA (1) | CA1209986A (en) |
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DK (2) | DK167765B1 (en) |
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US4619996A (en) * | 1984-07-09 | 1986-10-28 | Warner-Lambert Company | Process for preparing 2-β-D-ribofuranosylselenazole-4-carboxamide |
US4801698A (en) * | 1986-08-15 | 1989-01-31 | Warner-Lambert Company | Process for preparing diaminopyrimido(4,5-d)pyrimidine glycoside and glycotide |
US5438131A (en) * | 1992-09-16 | 1995-08-01 | Bergstrom; Donald E. | 3-nitropyrrole nucleoside |
GB9307043D0 (en) * | 1993-04-05 | 1993-05-26 | Norsk Hydro As | Chemical compounds |
US5907036A (en) * | 1995-02-17 | 1999-05-25 | Icn Pharmaceuticals, Inc. | Procedures for obtaining ribo-C-nucleosides |
NZ500831A (en) * | 1997-06-30 | 2001-06-29 | Icn Pharmaceuticals | Method of producing tiazofurin and other C-nucleosides using a single step process wherein the cyano sugar group is converted into thiocarboxamide and subsequently condensed to form an azole ring |
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US3423399A (en) * | 1966-06-09 | 1969-01-21 | Takeda Chemical Industries Ltd | Method for the production of 5'-ribonucleotide |
US3798209A (en) * | 1971-06-01 | 1974-03-19 | Icn Pharmaceuticals | 1,2,4-triazole nucleosides |
US3984396A (en) * | 1971-06-01 | 1976-10-05 | Icn Pharmaceuticals, Inc. | 1-(β,-D-ribofuranosyl)-1,2,4-triazole acid esters |
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